The phosphoinositol-3-kinase (PI3K) family, comprised of lipid kinases, is divided into three different classes: Class I, Class II, and Class III. The classifications are based on primary structure, regulation, and in vitro lipid substrate specificity. Class 1 PI3Ks are most extensively studied and they are activated by cell surface receptors, such as G-protein coupled receptors (GPCRs), growth factors and insulin. Class I PI3Ks are further classified into two subclass, IA and IB. PI3Ks IA enzymes are heterodimers consisting of a catalytic p110 subunit (α, β and δ) and a regulatory subunit (p85, p55, p50). PI3Ks IB enzyme family consists of one member, PI3 kinase γ. PI3K-α is involved in glucose metabolism and insulin signaling, whereas, PI3K-β is involved in platelets activation in thrombotic diseases. In contrast, PI3K-δ and PI3K-γ isoforms are mainly expressed in the hematopoietic systems. Pharmacological and genetic intervention have revealed that PI3K-δ is integral in the orchestration of both the innate and adaptive immune response including expression and activation of inflammatory mediators, inflammatory cell recruitment, airway remodeling and corticosteroid insensitivity in chronic inflammatory airway disease [Rommel C, et al. Nat. Rev. Lmmunol. 2007; 7(3):191-201; Medina-Tato D A, et. al. Immunology. 2007; 121(4):448-61 and Foster J G et. al. Pharmacol. Rev. 2012; 64(4):1027-54].
PI3K has been a validated target being explored by various pharma companies. For example, Idelalisib (Gilead), a PI3Kδ inhibitor, has been launched in 2014 for cancer treatment; however it carries black box warning (hepatotoxicity, severe diarrhea or colitis) and DDI risk (monitoring recommended for steroids; not recommended with salmeterol). GSK-2269557 (GlaxoSmithKline), a PI3Kδ specific inhibitor, has been in phase II for asthma and chronic obstructive pulmonary disease (COPD) as an inhaled product. Duvelisib (Infinity), PI3Kδ/γ dual inhibitor, has been discontinued in January 2015 (Phase II, Inhaled product for asthma and rheumatoid arthritis). PI3K δ/γ K/O mice showed severe impairment of thymocyte development (opportunistic infections). RV-1729 (RespiVert), another PI3Kδ/γ dual inhibitor, has been in phase I for asthma and COPD as an inhaled therapy. AMG-319 (Amgen), TGR-1202/RP-5264 (lncozen/TG therapeutics) and INCB040093 (Incyte) have been at different stages of development for treating lymphoid malignancy.
PI3K inhibitors, preferably PI3Kδ inhibitors have been disclosed in WO2012/082997, WO2012/037226, WO2012/007493, WO2012/107465, WO2011/058027, WO2010/136491, WO2010/138589, WO2010/044401, WO2009/146406, WO2009/045174, WO2009/045175, WO2009/053716 and GB2431156.
Also included herein by references are WO2012/104776, WO2010/005558, WO2010/114494, WO2009/100406, WO2009/034386 WO2008/116129, WO2005/000404 and WO2004035740. However, none of the cited reference disclose pyrazole derivatives as disclosed hereinafter.
Despite significant progress, there is an unmet need and huge opportunity for safe and orally efficacious phosphatidylinositol-3-kinase δ (PI3Kδ) inhibitors for treating and/or preventing inflammatory, autoimmune and hyperproliferative disease or disorder such as allergic asthma, severe asthma, steroid resistant asthma, COPD, psoriasis, psoriatic arthritis, rheumatoid arthritis multiple sclerosis, Systemic lupus erythematous or cancer. As a result of extensive research, the inventors of the present invention have identified safe and orally efficacious PI3Kδ inhibitors that can be used for said purpose.